Maintenance treatment of renal anaemia in haemodialysis patients with methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa administered monthly:a randomized comparative trial

Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly.

Deriving the Railway Mania

This article argues that the promotion boom which occurred in the railway industry during the mid 1840s was amplified by the issue of derivative-like assets, which let investors take highly leveraged positions in the shares of new railway companies. The partially paid shares which the new railway companies issued allowed investors to obtain exposure to an asset by paying only a small initial deposit. The consequence of this arrangement was that investor returns were substantially amplified, and many schemes could be financed simultaneously. However, when investors were required to make further payments it put a negative downward pressure on prices.

Entinostat prevents leukemia maintenance in a collaborating oncogene-dependent model of CN-AML.

The incidence of refractory acute myeloid leukemia (AML) is on the increase due in part to an aging population that fails to respond to traditional therapies. High throughput genomic analysis promises better diagnosis, prognosis and therapeutic intervention based on improved patient stratification. Relevant pre-clinical models are urgently required to advance drug development in this area. The collaborating oncogenes, HOXA9 and MEIS1, are frequently co-overexpressed in cytogenetically normal AML (CN-AML) and a conditional transplantation mouse model was developed that demonstrated oncogene-dependency and expression levels comparable to CN-AML patients. Integration of gene signatures obtained from the mouse model and a cohort of CN-AML patients using statistically significant connectivity Map (sscMap) analysis identified Entinostat as a drug with the potential to alter the leukemic condition towards the normal state. Ex vivo treatment of leukemic cells, but not age-matched normal bone marrow controls, with Entinostat validated the gene signature and resulted in reduced viability in liquid culture, impaired colony formation and loss of the leukemia initiating cell. Furthermore, in vivo treatment with Entinostat resulted in prolonged survival of leukemic mice. This study demonstrates that the HDAC inhibitor Entinostat inhibits disease maintenance and prolongs survival in a clinically relevant murine model of cytogenetically normal AML. © 2013 AlphaMed Press

Late-stage, primary open-angle glaucoma in Europe:Social and health care maintenance costs and quality of life of patients from 4 countries

Objective: The purpose of this study was to estimate costs and quality of life (QoL) of late-stage glaucoma patients in 4 European countries. Methods: Retrospective review of medical charts of patients with POAG who were followed in a low-vision or vision rehabilitation center in one of 4 countries for at least 1 year was used to determine patient characteristics, health status, and health care resource use. Visual impairment was measured by best-corrected visual acuity (Snellen score). Patients were also interviewed over the telephone in order to assess their health-related QoL (using EuroQol EQ-5D) and use of resources including: the number of visits to rehabilitation centers, visits to hospital and non-hospital specialists, the use of low-vision devices, medication, tests, and the use of hired home help. The costs associated with resource use were calculated from the perspective of a third-party payer of health and social care based on resource usage and unit costs in each country. Results: Patients undergoing visual rehabilitation in France (n=21), Denmark (n=59), Germany (n=60), and the United Kingdom (n=22) were identified, interviewed and had their medical charts reviewed. Annual maintenance costs of late-stage glaucoma amounted to €830 (±445) on average. Average home help costs were more than 3 times higher. QoL, on average, was 0.65 (±0.28). QoL was positively correlated with the level of visual acuity in the patients' best eye. On the other hand, visual acuity was also positively correlated to health care costs, but negatively correlated to costs of home help. Conclusions: The study was limited by its observational, uncontrolled design. The finding that late-stage glaucoma is associated with higher home help costs than health care maintenance costs suggests that potential savings from a better preventive treatment are to be found for social care payers rather than health care payers. © 2008 Informa UK Ltd All rights reserved.

Online Multiperson Tracking With Occlusion Reasoning and Unsupervised Track Motion Model

We address the problem of multi-target tracking in realistic crowded conditions by introducing a novel dual-stage online tracking algorithm. The problem of data-association between tracks and detections, based on appearance, is often complicated by partial occlusion. In the first stage, we address the issue of occlusion with a novel method of robust data-association, that can be used to compute the appearance similarity between tracks and detections without the need for explicit knowledge of the occluded regions. In the second stage, broken tracks are linked based on motion and appearance, using an online-learned linking model. The online-learned motion-model for track linking uses the confident tracks from the first stage tracker as training examples. The new approach has been tested on the town centre dataset and has performance comparable with the present state-of-the-art

Killer immunoglobulin-like Receptors (KIR) haplogroups A and B track with Natural Killer Cells and Cytokine Profile in Aged Subjects: Observations from Octo/Nonagenarians in the Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST)

Background: Natural Killer Cells (NK) play an important role in detection and elimination of virus-infected, damaged or cancer cells. NK cell function is guided by expression of Killer Immunoglobulin-like Receptors (KIRs) and contributed to by the cytokine milieu. KIR molecules are grouped on NK cells into stimulatory and inhibitory KIR haplotypes A and B, through which NKs sense and tolerate HLA self-antigens or up-regulate the NK-cytotoxic response to cells with altered HLA self-antigens, damaged by viruses or tumours. We have previously described increased numbers of NK and NK-related subsets in association with sIL-2R cytokine serum levels in BELFAST octo/nonagenarians. We hypothesised that changes in KIR A and B haplotype gene frequencies could explain the increased cytokine profiles and NK compartments previously described in Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) octo/nonagenarians, who show evidence of ageing well.

Results: In the BELFAST study, 24% of octo/nonagenarians carried the KIR A haplotype and 76% KIR B haplotype with no differences for KIR A haplogroup frequency between male or female subjects (23% v 24%; p=0.88) or for KIR B haplogroup (77% v 76%; p=0.99). Octo/nonagenarian KIR A haplotype carriers showed increased NK numbers and percentage compared to Group B KIR subjects (p=0.003; p=0.016 respectively). There were no KIR A/ B haplogroup-associated changes for related CD57+CD8 (high or low) subsets. Using logistic regression, KIR B carriers were predicted to have higher IL-12 cytokine levels compared to KIR A carriers by about 3% (OR 1.03, confidence limits CI 0.99–1.09; p=0.027) and 14% higher levels for TGF-ß (active), a cytokine with an anti-inflammatory role, (OR 1.14, confidence limits CI 0.99–1.09; p=0.002).

Conclusion: In this observational study, BELFAST octo/nonagenarians carrying KIR A haplotype showed higher NK cell numbers and percentage compared to KIR B carriers. Conversely, KIR B haplotype carriers, with genes encoding for activating KIRs, showed a tendency for higher serum pro-inflammatory cytokines compared to KIR A carriers. While the findings in this study should be considered exploratory they may serve to stimulate debate about the immune signatures of those who appear to age slowly and who represent a model for good quality survivor-hood.© 2013 Rea et al.; licensee BioMed Central Ltd.

Automated Methods for Virtual Maintainability & Aerospace Maintenance Planning

Abstract. Modern business practices in engineering are increasingly turning to post manufacture service provision in an attempt to generate additional revenue streams and ensure commercial sustainability. Maintainability has always been a consideration during the design process but in the past it has been generally considered to be of tertiary importance behind manufacturability and primary product function in terms of design priorities. The need to draw whole life considerations into concurrent engineering (CE) practice has encouraged companies to address issues such as maintenance, earlier in the design process giving equal importance to all aspects of the product lifecycle. The consideration of design for maintainability (DFM) early in the design process has the potential to significantly reduce maintenance costs, and improve overall running efficiencies as well as safety levels. However a lack of simulation tools still hinders the adaptation of CE to include practical elements of design and therefore further research is required to develop methods by which ‘hands on’ activities such as maintenance can be fully assessed and optimised as concepts develop. Virtual Reality (VR) has the potential to address this issue but the application of these traditionally high cost systems can require complex infrastructure and their use has typically focused on aesthetic aspects of mature designs. This paper examines the application of cost effective VR technology to the rapid assessment of aircraft interior inspection during conceptual design. It focuses on the integration of VR hardware with a typical desktop engineering system and examines the challenges with data transfer, graphics quality and the development of practical user functions within the VR environment. Conclusions drawn to date indicate that the system has the potential to improve maintenance planning through the provision of a usable environment for inspection which is available as soon as preliminary structural models are generated as part of the conceptual design process. Challenges still exist in the efficient transfer of data between the CAD and VR environments as well as the quantification of any benefits that result from the proposed approach. The result of this research will help to improve product maintainability, reduce product development cycle times and lower maintenance costs.

Improving MTM-UAS to predetermine automotive maintenance times

The preventive knowledge of serviceability times is a critical factor for the quantification of after-sales services costs of a vehicle. Predetermined motion time system are frequently used to set labor rates in industry by quantifying the amount of time required to perform specific tasks. The first such system is known as Methods-time measurement (MTM). Several variants of MTM have been developed differing from each other on their level of focus. Among them MTM-UAS is suitable for processes that average around 1-3 min. However experimental tests carried out by the authors in Elasis (Research Center of FIAT Group) demonstrate that MTM-UAS is not the optimal approach to measure serviceability times. The reason is that it doesn't take into account ergonomic factors. In the present paper the authors propose to correct the MTM-UAS method including in the task analysis the study of human postures and efforts. The proposed approach allows to estimate with an "acceptable" error the time needed to perform maintenance tasks since the first phases of product design, by working on Digital Mock-up and human models in virtual environment. As a byproduct of that analysis, it is possible to obtain a list of maintenance times in order to preventively set after-sales service costs. © 2012 Springer-Verlag.

Role of nitric oxide in maintenance of basal oral tissue blood flow in anesthetized cats

Experiments were undertaken to determine if nitric oxide (NO) plays a role in regulation of basal blood flow in the oral cavity of pentobarbital anesthetized cats and, if so, to quantify this effect using dose-response relationships. Blood flow was continuously measured from the surface of the tongue and mandibular gingiva (laser-Doppler flowmetry) and from the lingual artery (ultrasonic flowmetry). Cardiovascular parameters also were recorded. Administration of the nonselective inhibitor of nitric oxide synthase (NOS), L-NAME (0.08-20 mg/kg i.v.), produced a dose-related increase of blood pressure associated with decreases of blood flow at all three measurement sites. Maximal blood flow depression of 50-60% was seen 30-60 min after administration of 1.25 mg/kg of L-NAME. D-NAME (1.25 mg/kg i.v.) was inactive at all sites. Subsequent administration of L-arginine partially reversed effects of L-NAME in the lingual artery and tongue, but not in the gingival circulation. The neuronally selective NOS inhibitor, 7-nitroindazole (7-NI, 30 mg/kg i.p.), was devoid of effect on any of the measured parameters. These results suggest that endothelial (but not neuronally derived) NO plays an important role in control of basal blood flow in oral tissues of the cat.

PTEN Phosphatase-Independent Maintenance of Glandular Morphology in a Predictive Colorectal Cancer Model System

Organotypic models may provide mechanistic insight into colorectal cancer (CRC) morphology. Three-dimensional (3D) colorectal gland formation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN) coupling of cell division cycle 42 (cdc42) to atypical protein kinase C (aPKC). This study investigated PTEN phosphatase-dependent and phosphatase-independent morphogenic functions in 3D models and assessed translational relevance in human studies. Isogenic PTEN-expressing or PTEN-deficient 3D colorectal cultures were used. In translational studies, apical aPKC activity readout was assessed against apical membrane (AM) orientation and gland morphology in 3D models and human CRC. We found that catalytically active or inactive PTEN constructs containing an intact C2 domain enhanced cdc42 activity, whereas mutants of the C2 domain calcium binding region 3 membrane-binding loop (M-CBR3) were ineffective. The isolated PTEN C2 domain (C2) accumulated in membrane fractions, but C2 M-CBR3 remained in cytosol. Transfection of C2 but not C2 M-CBR3 rescued defective AM orientation and 3D morphogenesis of PTEN-deficient Caco-2 cultures. The signal intensity of apical phospho-aPKC correlated with that of Na/H exchanger regulatory factor-1 (NHERF-1) in the 3D model. Apical NHERF-1 intensity thus provided readout of apical aPKC activity and associated with glandular morphology in the model system and human colon. Low apical NHERF-1 intensity in CRC associated with disruption of glandular architecture, high cancer grade, and metastatic dissemination. We conclude that the membrane-binding function of the catalytically inert PTEN C2 domain influences cdc42/aPKC-dependent AM dynamics and gland formation in a highly relevant 3D CRC morphogenesis model system.

Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability

Mutations within BRCA1 predispose carriers to a high risk of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through the assembly of multiple protein complexes involved in DNA repair, cell-cycle arrest, and transcriptional regulation. Here, we report the identification of a DNA damage-induced BRCA1 protein complex containing BCLAF1 and other key components of the mRNA-splicing machinery. In response to DNA damage, this complex regulates pre-mRNA splicing of a number of genes involved in DNA damage signaling and repair, thereby promoting the stability of these transcripts/proteins. Further, we show that abrogation of this complex results in sensitivity to DNA damage, defective DNA repair, and genomic instability. Interestingly, mutations in a number of proteins found within this complex have been identified in numerous cancer types. These data suggest that regulation of splicing by the BRCA1-mRNA splicing complex plays an important role in the cellular response to DNA damage.

A predictive maintenance system for integral type faults based on support vector machines:An application to ion implantation

In semiconductor fabrication processes, effective management of maintenance operations is fundamental to decrease costs associated with failures and downtime. Predictive Maintenance (PdM) approaches, based on statistical methods and historical data, are becoming popular for their predictive capabilities and low (potentially zero) added costs. We present here a PdM module based on Support Vector Machines for prediction of integral type faults, that is, the kind of failures that happen due to machine usage and stress of equipment parts. The proposed module may also be employed as a health factor indicator. The module has been applied to a frequent maintenance problem in semiconductor manufacturing industry, namely the breaking of the filament in the ion-source of ion-implantation tools. The PdM has been tested on a real production dataset. © 2013 IEEE.